EDECIO CUNHA NETO

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Departamento de Clínica Médica, Faculdade de Medicina - Docente
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/60 - Laboratório de Imunologia Clínica e Alergia, Hospital das Clínicas, Faculdade de Medicina - Líder

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Revista / Livro: European Heart Journal ×

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  • article 2 Citação(ões) na Scopus
    4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification
    (2023) KIYUNA, Ligia A.; CANDIDO, Darlan S.; BECHARA, Luiz R. G.; JESUS, Itamar C. G.; RAMALHO, Lisley S.; KRUM, Barbara; ALBUQUERQUE, Ruda P.; CAMPOS, Juliane C.; BOZI, Luiz H. M.; ZAMBELLI, Vanessa O.; ALVES, Ariane N.; CAMPOLO, Nicolas; MASTROGIOVANNI, Mauricio; BARTESAGHI, Silvina; LEYVA, Alejandro; DURAN, Rosario; RADI, Rafael; ARANTES, Guilherme M.; CUNHA-NETO, Edecio; MORI, Marcelo A.; CHEN, Che-Hong; YANG, Wenjin; MOCHLY-ROSEN, Daria; MACRAE, Ian J.; FERREIRA, Ludmila R. P.; FERREIRA, Julio C. B.
    Background and Aims Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure.Methods Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets.Results 4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure.Conclusions 4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure. Structured Graphical Abstract The vicious cycle of heart failure (HF). (i) Impaired aldehyde metabolism by aldehyde dehydrogenase 2 (ALDH2); (ii) accumulation of 4-hydroxynonenal (4-HNE), a reactive aldehyde by-product of mitochondrial dysfunction; (iii) direct 4-HNE inhibition of Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis; and (iv) overall impairment of miRNA biogenesis, which negatively impacts HF outcome. Blue and red arrows/inhibitors represent the vicious cycle of HF and the benefits of small molecule activators of ALDH2 in HF, respectively.
  • conferenceObject
    Benznidazole treatment is associated with Trypanosoma cruzi blood PCR negativity and less cardiac lesions in Chagas disease: NIH SaMitrop Study
    (2017) CARDOSO, C. S.; SABINO, E. C.; OLIVEIRA, C. D. L.; OLIVEIRA, L. C.; FERREIRA, A. M.; BIERRENBACH, A. L.; SILVA, J. L. P.; COLOSIMO, E. A.; CUNHA-NETO, E.; RIBEIRO, A. L. P.
  • conferenceObject
    Endothelial inflammatory activation is related to myocardial perfusion disturbance in experimental chronic Chagas disease
    (2022) TANAKA, D. M.; FABRICIO, C. G.; MARIN-NETO, J. A.; BARROS-FILHO, A. C. L.; LOPES, C. D.; OLIVEIRA, L. F. L.; MEJIA, J.; ALMEIDA, R. R.; BATAH, S. S.; NEKOLLA, S. G.; HIGUCHI, M. L.; CUNHA-NETO, E.; FABRO, A. T.; ROMANO, M. M.; SIMOES, M. V.
  • conferenceObject
    Rest myocardial perfusion disturbance is related to inflammation but not to fibrosis inexperimental chronic chagas cardiomyopathy
    (2013) OLIVEIRA, L. F. L.; CARVALHO, E. E. V.; MEJIA, J.; SANTANA-SILVA, J.; ROMANNO, M. M. D.; CUNHA-NETO, E.; HIGUCHI, M. L.; MACIEL, B. C.; MARIN-NETO, J. A.; SIMOES, M. V.
  • conferenceObject
    The predictive value of plasma Galectin-3 for cardiac impairment and mortality in patients with Chagas disease
    (2016) FERNANDES, F.; MOREIRA, C. H.; OLIVEIRA, L. C.; IANNI, B. M.; LORENZO, C. D.; RAMIRES, F. J. A.; NASTARI, L.; RIBEIRO, A. L. P.; CUNHA NETO, E.; SABINO, E. C.; MADY, C.
  • conferenceObject
    Circulating miRNA-770-5p and miRNA-30d-5p as potential biomarkers in vasoplegic syndrome after on-pump coronary artery bypass surgery - PREVENT trial
    (2022) MEJIA, O. A. V.; SOUZA, R. C.; MENEGHINI, B.; SANTOS, A. S.; LISBOA, L. A. F.; DALIAN, L. A. O.; CUNHA-NETO, E.; FERREIRA, L. R. P.; JATENE, F. B.
  • conferenceObject
    Lack of effect of simvastatin on structural remodeling in animal model of chagas cardiomyopathy
    (2012) IANNI, B. M.; RAMIRES, F. J. A.; SALEMI, V. M. C.; FERNANDES, F.; OLIVEIRA, A. M.; PESSOA, F. G.; FONSECA, K. C. B.; CUNHA NETO, E.; MADY, C.
    Purpose: Chagas cardiomyopathy(CM)is characterized by a large amount of fibrosis and inflamation. As simvastatin (simva) has anti-inflamatory effects, we hypothetized that it could be an important drug in the treatment of patients with CM. The purpose was to evaluate simva in the myocardium remodeling and inflammation in an animal model of CM. Methods: 123 hamsters were divided:C-controls (25), CSimva-controls with simva 10mg/kg/day (25), Simva1-infected treated from the beginning with the same dose of simva (25), Simva2-infected treated after 4 months (24); Infectuntreated(24). Follow-up of 10 months. Interstitial collagen volume fraction (ICVF) RV and LV measured using videomorphometry and picrosirius red stained heart. Metalloproteinase 9 (MMP9) was obtained by zymography. Gene expression of TNFalpha, IFNgamma, IL10 by real time PCR and Ct. Survival by Kaplan-Meierand log rank. Comparison between groups by Kruskal-Wallis; p≤0.05. Results: Infected animals (Simva1=189±133days; Simva2=150±124;Infect=138±123) lived less than controls (C=257±80; CSimva=283±58)(p≤0.05) with no difference among infected. ICVF-RV (%) was greater in infected groups (Simva1=3.88±1.14; Simva2=2.22±0.64; Infect=4.38±0.83)than in controls (C=1.12±0.31; CSimva=2.18±0.73) (p≤0.05) with no difference among infected groups. ICVF-LV (%) was greater in infected animals (Simva1=1.83±1.01, Simva2=1.52±0.93; Infect=3.01±0.66) than in controls (C=0.68±0.31; CSimva=0.81±0.28) (p≤0.05) with no difference among infected. MMP9 was higher in infected groups (Simva1=2394±2441, Simva2=5673±4091; Infect=2392±2042) compared to controls (C=954±2332;CSimva=454±1123) (p≤0.05) with no difference among infected. TNFal-pha did not have difference among infected groups (Simva1=5.33±3.66,Simva2=4.44±2.17; Infect=6.13±3.24). IFNgamma in infected groups (Simva1=5.47±3.56, Simva2=4.46±2.08; Infect=4.21±2.09) was higher than in controls (C=8.50±2.59; CSimva=6.84±2.53) (p≤0.05) with no difference among infected. IL10 in infected animals (Simva1=9.07±4.62, Simva2=7.76±4.77;Infect=8.11±4.48) did not have difference and the values were greater than controls (C=14.11±4.40; CSimva=12.55±3.90) (p≤0.05). Conclusions: Simva did not attenuate deposition of interstitial collagen,did not change dynamics of collagen degradation,did not decrease inflammation,and did not reduce mortality.
  • conferenceObject
    Regional myocardial perfusion disturbance in experimental model of chronic Chagas cardiomyopathy
    (2017) OLIVEIRA, L. F. L.; CARVALHO, E. E. V.; ROMANO, M. M. D.; MEJIA, J.; TANAKA, D. M.; ABDALLA, D. R.; MALAMUT, C.; THACKERAY, J. T.; BENGEL, F. M.; WICHERT-ANA, L.; HIGUCHI, M. L.; CUNHA-NETO, E.; SCHMIDT, A.; MARIN-NETO, J. A.; SIMOES, M. V.